On The Cover/Top Stories
Targeting Melanoma
Robert Langreth 10.15.07, 12:00 AM ET
A new arsenal of therapies is aimed at a widespread and lethal skin cancer.
"Until recently researchers had little clue what molecular changes drive melanoma's rapid growth. But that has changed in a flurry of basic biology findings. "In terms of understanding what makes melanoma tick, in the past five years there has been an utter revolution," says Keith Flaherty, a physician at the University of Pennsylvania.
In 2002 gene researchers in the U.K. discovered that two-thirds of melanomas have a mutation in a growth-promoting gene inside skin cells called BRAF. The mutation causes the BRAF protein to become stuck in the "on" position, so it constantly sends a signal to the nucleus that it is time to proliferate. BRAF blockers are now in early-stage human trials at Novartis and separately at Roche, which works with partner Plexxikon. AstraZeneca is in midstage trials with 180 melanoma patients for a drug that hits a related target called mitogen-activated protein kinase kinase. "Every company I know of is interested in this," says Plexxikon Chief Executive Peter Hirth.
Therapies that trick the immune system into attacking melanoma are further along. Such immune system boosters have the potential to treat many types of cancer, but melanoma is one of the prime initial targets because it is one of the few cancers known to go into spontaneous remission on its own, indicating a possible immune response at work. The immune system activator interleukin-2 helps 15% of advanced melanoma cases and cures a few, but it produces such devastating side effects that patients must be hospitalized.
Pfizer's drug tremelimumab and Bristol-Myers Squibb's ipilimumab are antibodies to a protein called CTLA-4 (cytotoxic T-lymphocyte antigen-4) that acts as an emergency brake to prevent killer T cells from attacking healthy tissue. The antibodies bind to the CTLA-4, found on a cell's surface, and shut off the brake. Killer T cells then attack the cancer cells. Both drugs are in final-stage trials on hundreds of melanoma patients.
Much credit for the concept goes to immunologist James Allison, now at Sloan-Kettering. In the mid-1990s he theorized that CTLA-4 might prevent the immune system from mounting an effective response against tumors. Others were skeptical. But Allison showed in 1996 that he could shrink tumors in mice by injecting them with antibodies to CTLA-4.
Both Pfizer and Medarex, a biotech firm in Princeton, N.J., subsequently produced human antibodies to CTLA-4 and began testing them in patients a few years later. In 2005 Bristol-Myers Squibb paid Medarex $50 million in cash plus up to $480 in payments contingent on the success of Medarex's antibody.
At a meeting of cancer specialists last June Bristol-Myers and Medarex reported their drug shrank tumors in 46, or 13%, of 356 melanoma patients. The Pfizer antibody shrank melanomas in 7 of 84 patients in a midstage trial. The success rates were modest, but cancer doctors say that some patients may have had delayed responses. In some people tumors started to regress months after they had been declared treatment failures, says Bristol-Myers Vice President Renzo Canetta.
UCLA's Ribas calls the response rates "very low" and cautions that the anti-CTLA-4 drugs are just a first step. But even if the drugs improve survival only minimally, they are likely to be approved, he says. Bristol-Myers and Medarex are expected to finish key trials this fall. RBC Capital Markets analyst Jason Kantor pegged the odds of disappointing results "relatively high" in a recent report and rated Medarex an underperform; if the response rate is under 10%, it would make near-term approval "iffy", he says. Side effects of the drugs can include inflammation of the colon, thyroid or pancreas, or other autoimmune problems.
One reason for the limited response rate may be that some patients' T cells do a poor job of recognizing melanoma. To improve this situation, researchers are combining new antimelanoma vaccines with anti-CTLA-4 drugs. The idea is that the vaccines will train T cells to spot cancer, while the antibody will make sure the T cells remain activated long enough to do their dirty work.
Sharon Belvin was one of the first to try such a combination therapy. In May 2004, just a week before her wedding, she had developed a melanoma metastasis in her left lung. Belvin was only 22. The tumor grew through her chest cavity underneath her collarbone. Various chemo drugs and interleukin-2 produced nerve damage and other nasty side effects and didn't solve the problem. By June 2005 she had tumors in both lungs and could barely breathe or walk. Then Wolchok put her in a trial testing ipilimumab with an experimental Medarex vaccine. After only four treatments the tumors started to melt away. They were gone by mid-2006. The Jamesville, N.C. resident has been off therapy for a year and is pregnant with her first child, a girl due Feb. 10 2008."
By the Numbers
59,940 annual cases of melanoma in the U.S.
8,110 annual deaths.
99% five-year survival rate, localized disease.
15% five-year survival rate, widespread disease.
Source: American Cancer Society
Take Care,
Jimmy B
No comments:
Post a Comment